The development of a simple, high-yielding chain extension reaction that facilitates the preparation of heavily functionalized, amino acid-derived ?-keto esters is proposed. The utility of this method is anticipated for the preparation of ketomethylene and hydroxyethylene peptide isosteres. The methodology will be modified to allow the preparation of a variety of alternative peptide isosteres, including those that possess embedded tetrahydrofuran and embedded pyrrolidine rings. These cyclic isosteres are attractive peptide mimics, in that the hydrogen bonding functionality that mimics the amide carbonyl is presented and restricted rotation imposed by the ring provides conformational rigidity. Two novel variations to the chain extension protocol have been developed that result in the formation of cyclopropyl alcohols. The scope and utility of this methodology will be probed as it applies to peptide isostere formation, general synthetic methodology, and application to natural product synthesis. PUBLIC HEALTH RELEVANCE: The synthetic methodology described in this proposal will provide tools for the medicinal chemist in the preparation of molecules of biological interest. Since a large number of pharmaceutical agents are designed to mimics peptide skeletons, this methodology should find utility in a broad number of therapeutic arenas.